Process of preparing allylic substituted 9-fluorenecarboxylic acids



' carb'oxylic acid.

Patented Oct. 17, 1950 c, ,5; 7

UNITED STATE PROCESS 2,526,109 OF PREPARING ALLYLIC SUBSTI- TUTEDB-FLUORENECARBOXYLIC ACIDS Richard T. Arnold,

St. Paul, Minn.

' No'Drawing. Application April 11, 1949,

Serial No.

I 6 Claims, (01.

The present invention relates to the introduction of allylic groups intothe Q-positiori of 9-fiuorenecarboxylic acid. These compounds are usefulin various organic syntheses, and particularly in the production ofpharmaceutical compounds 5 having activity as analgesics,antispasmodics, anesthetics, etc. j

Broadly, the invention involves the rearrangement of an allylic ester ofQ-fluorenecarboxylic acid such that the allyl group is introduced intothe 9-position. This reaction, is found to occur in the presence ofbasic reagents. I

It is therefore an object of the present inven-' tion to provide aprocess for the introduction of allylic groups into the 9-po'sition of9-fluorene- V The invention involves the conversion of esters of thefollowing type l 2 R3 into allylic substituted9-fiuorenecarboirylicacids havin the following'formula i i anion of thedesired acid. This is shown by the following reactions: 50

I portance in the (B=basic reagent) l Rearrangement are, capable ofefiecting the desired ionizationof the original e'stermIn general,hydrides, amides, substituted amides, and alkoxides of active'metalssuch as sodium, potassium, lithium,- and the like, and also Grignardreagents, will bring about this rearrangement of allylicv esters.Suitable basic reagents include the following: NaH', KH, NaNHz,

KOC(CH3) 3, and'RMgX, where, R is alkyl or aryl and X is Cl, Br, or I.

. As will be seen from the reactiongivenaboye, I the allylic groupundergoes an inversion in the course of the rearrangement. This is fno'impreparation of simple allyl compounds. It is of importance; however,in the preparation of substituted allyl 'compounds in which; forexample, N crotyl and iso-crotyl, 9-

fluorenecarboxylates are employed; Thus the present invention makespossible the preparation of compounds in substantially pure form whichare diflicult, if not impossible,-to'prepare in any other manner.

The reaction maybe carried out preferablyunder. anhydrous conditions bysimply mixing the 'allyl ester with-the basic reagent ina suitable inertsolvent, which includes ethers such as diethyl ether, dioxane; a widevariety of hydrocar- 'bons such as benzene, toluene, petroleum ether andthe like; and alcohols when their alkoxides are employed as the basicreagent. In some instances, the reaction'is exothermic and proceedswithout'the application of heat. In other m 3 stances it may bedesirable to warm the reaction mixture under reflux for a short periodof time, and then allow an extended period of time for the reaction tobe carried out. Considerable variation is therefore possible in thespecific reaction conditions which may be employed, depending upon theparticular ester, the basic reagent, the solvent, and the like.

The following example will serve to illustrate the invention:

EXAMPLE Preparation of Q-fluorenecarboxylic acid A solution of 22.8 g.(0.10 mole) of benzilic acid in 350 ml. of dry, thiophene-free benzenewas same cooled in ice and the crystalline mass which re- 7 sulated Wastreated with 40.0 g. (0.30 mole) of anhydrous aluminum chloride. Themixture was thoroughly shaken, then heated under reflux for three hours.Large quantities of hydrogen chloride were evolved. The resulting darkred solution was cooled and was cautiously decomposed by the addition ofsmall pieces of ice. The mixture was diluted with 200 ml, of water and100 m1. of concentrated hydrochloric acid and the benzene was distilledfrom the mixture. The product was separated by filtration; all the lumpswere crushed; then the product was extracted by boiling with 200 ml. of10% sodium carbonate so lution. This extraction was repeated on theundissolved residue with 100 m1. of 10% sodium car bonate solution. Thebasic filtrates were strongly acidified with concentrated hydrochloricacid, and the resulting suspension was digested on the steam bath forone-half hour. By filtration 21.0 g. (quantitative yield) of 9-fiuorenecarboxylic acid, M. P. 200225 C., was obtained. To purify the product,the dry acid was suspended in 100 ml. of benzene; the mixture was warmedon the steam bath; the product was recovered by filtration and washed onthe filter with ml. of benzene and finally with petroleum ether (13.P-.'28- 38 C.). In this way 17.3 g. (82.5%) of 9-fluorenecarboxylicacid, M. P; 226-229 C., was ob tained. The melting points reported forthis compound range from 220 to 232 C.

Preparation of allyl 9-fluoreriecarbomylate A'mixtureof 173g. of'9-fluorenecarboxylic acid and g. of purified thionyl chloride washeated under reflux for 45 minutes. The excess thionyl chloride wasremoved in vacuo. The residue was dissolved. in m1. of drycarbontetrachloride. The solution was cooled in an ice bath, treatedwith a mixture of 20 ml. of pyridine and 25 g, of allyl alcoholfandallowed to stand overnight. The resulting solution was washed with 500ml. of water, ml. of dilute (71 100) hydrochloric acid, 10 ml. of 10%sodium bicarbonate solution, and finally with 200 ml. of Water. Theorganic layer was dried over magnesium sulfate; the solvents wereremoved; and the residue was distilled at 3 mm. The fractions distillingbetween and C. at 3 mm. weighed 10.5 g. (50.7%), n =L6000 to 1.6022. Acenter fraction was redistilled for analysis, 13. P. 174 C. at 2 mm., n=1.6012. i v

AnaZ.Calcd. for Cl'7Hl4-O2I C, 81.58; LEI/5.64:. Found: C, 81.84; H,5.92.

A direct esterification of 20.0 g. of 9-fluorenecar'boxylic acid bheating it under reflux over night with 200 ml. of allyl alcohol and 1.0g. of ptoluenesulfonic acid produced 12.2 g. (51.2%) of allyl'9-fluorenecarboxylate.

Preparation of 9-allyl-9-fiuorenecarbomylic acid toluene, and 0.92g.(0.04 mole) of lithium amide was heated under reflux for three hours.The mixture was cooled, and 5 ml. of ethanol Was added to destroy theexcess lithium amide. The resulting solution was washed into aseparatory funnel with alternate portions of water and ether. Theorganic layer was extracted with three 10 ml. portions of 10% sodiumhydroxide. The combined aqueous solutions were extracted with ether.Acidification of the alkaline solution with concentrated hydrochloricacid precipitated 2.18 g. (97.5%) of 9-allyl-9-fluorenecarboxylic acid,M. P. 129.5-131 C. The acid, after crystallization from petroleum ether(B. P. 60-70 C.), melted at 131.5-132.5 C. A mixture with an authenticsample of 9*-allyl-9-fluorenecarboxylic acid prepared according to themethod of Wislicenus and Mocker (Ben, 46, 2772 (1913)), showed nodepression of melting point.

AnaZ;-'Calcd. for C1'7H14021 C, 81.58; H, 5.64. Found: C, 81.85; H,5.62.

I claim as my invention:

1. Process of preparing allylic substituted '9-fiuorene'carboxylic acidhaving the following formula CH='CC'Ef{ COOH 1 R2 R3 in which R1, R2,and are selected from the group consisting of hydrogen and aliphatichydrocarbon radicals, which comprises reacting an ester having thefollowing formula I" T H 7 H ooolon-c=oH R1 R2 R3 with an active metalhydride capable of converting said ester to an anion, and rearrangingsaid anion to introduce theallyl group into the 9-pcsi- 'tion. 1 a 2.Process of preparing allylic substituted 9-fiuorenecarboxylic acidhaving the following formula I in which R1, R2, and R3 are selected fromthe group consisting of hydrogen and aliphatic hydrocarbon radicals,which comprises reacting an ester having the following formula 6 r withan active metal alkoxide capable of converting said ester to an anion,and rearranging said anion to introduce the 'allyl group into the9-position. 7

3. Process of preparing allylic substituted 9-fluorenecarboxy1ic acidhaving the following formula R1 R2 3 i V in which R1, R2, and R3 areselected from the group consisting of hydrogen and aliphatic hydrocarbonradicals, which comprises reacting an ester having the following formulawith an active metal amide capable of converting said ester to an anion,and rearranging said anion to introduce the allyl group into the9-position. V r

4. Process according to claim 3 in which the active metal amide islithium amide.

5. Process of preparing 9-allyl-9-fluorenecarboxylic acid whichcomprises reacting allyl 9- fluorenecarboxylate with lithium amide toconvert said ester to an anion, and rearranging said anion to produce 9-allyl-9fluorenecarboxy1ic acid.

6. Process of preparing allylic substituted 9-fluorenecarboxylic acidshaving the following formula 0H=Cofi GO0H R1 R1 R3 in which R1, R2, and.R3 are selected from the group consisting of hydrogen and aliphatichydrocarbon radicals, which comprises reacting an ester having thefollowing formula R1 R2 3 with a basic reagent capable of convertingsaid ester to an anion, said basic reagent bein selected from the groupconsisting of active metal hydrides, active metal alkoxides, activemetal amides, and Grignard reagents, and rearrangingsaid anion tointroduce the allyl group into the 9-position.

RICHARD T. ARNOLD.

REFERENCES CITED The. following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date OTHER REFERENCES Kimel et al.:Chem. Abstracts, vol. 38, col. 66 (1944).

Adams et al.: Organic Reactions (Wiley). v01. 2, pages 2-6 (19%), 1

Groll et a1. June 27, 1939

6. PROCESS OF PREPARING ALLYLIC SUBSTITUTED 9-FLUORENECABOXYLIC ACIDSHAVING THE FOLLOWING FORMULA